Alzheimer's drug developers to get new FDA marching orders

Existing drugs to treat Alzheimer's disease have had to show that… (Rich Pedroncelli )

Experimental drug treatments promising to slow or reverse the progression of Alzheimer's disease will need to be assessed with a new and more subtle set of rules, a pair of FDA officials wrote this week. The resulting new guidelines, predict some researchers, should allow Alzheimer's drugs under development to travel a faster path to the U.S. market -- and to the more than 5 million Americans who need them.

The new guidelines, issued to drug developers last month and outlined this week in the New England Journal of Medicine, reflect a growing shift among both physicians and researchers toward earlier detection and treatment of the memory-robbing disease. As research has begun to uncover the mysterious ways in which Alzheimer's disease takes root and progresses, brain scientists and neurologists have come to recognize that by the time a patient shows clear signs of dementia, it may be too late to change the course of the disease.

But if early treatment approaches are to alter the progression of Alzheimer's disease in those who are not yet in the grips of dementia, they will have to be judged differently than existing medications have been, wrote Dr. Nicholas Kozauer and Dr. Russell Katz in the New England Journal of Medicine this week. Kozauer and Katz assess neurological drugs for the FDA's Division of Drug Evaluation and Research.

Existing medications -- prescriptions drugs such as memantine (marketed as Namenda) and cholinesterase inhibitors (sold under the commercial names Aricept, Exelon, Razadyne and Cognex) -- were developed when far less was known about Alzheimer's disease progression, and they were judged effective if they helped Alzheimer's patients function better in simple tasks of daily living. For patients with clear dementia symptoms, clinical trials had to show that the medications marginally improved the ability to bathe, eat, cook and maintain a daily schedule with minimal help.

But Alzheimer's disease drugs still in development will have more ambitious goals, and they'll be designed for use in patients who have not yet descended into dementia, Kozauer and Katz wrote. Accordingly, in assessing their effectiveness, the FDA must be willing to consider other, more subtle benefits they may provide: They may maintain or improve a patient's power to reason, to follow complex directions, to recall recent events and integrate them into a lifetime of learning.

Other experimental medications may have to be judged on their ability to influence "surrogate endpoints" such as the build-up of abnormal proteins in the brain -- even if that does not immediately translate into improved cognition, the FDA officials wrote.

In fields such as cardiology, measures such as blood pressure and trigycerides have long been recognized as "surrogates" for heart attack and stroke. So drugs approved to prevent heart attack and stroke are often approved entirely on their ability to change patients' blood pressure and cholesterol profile.

Research is refining just exactly how the physiological hallmarks of Alzheimer's Disease -- neurofibrillary tangles and amyloid plaques in the brain -- are linked to a patient's loss of memory and reasoning. And as that relationship becomes clearer, drugs that slow the development of those tangles and plaques may get the nod even if their makers cannot demonstrate immediate improvement in a patient's cognition.

The rules that guide the FDA's approval process for Alzheimer's disease "should evolve" along with such research, Kozauer and Katz wrote. In many cases, new drugs for Alzheimer's may be approved for marketing even as they are being further studied and refined, they added.

William H. Frey II, director of Alzheimer's Research Center at Regions Hospital in St. Paul Minnesota, said the FDA's new framework for assessing Alzheimer's drugs will facilitate the approval of more treatments, and a wider variety of treatment approaches. And because the new framework will draw pharmaceutical company support to experimental drug efforts, those treatments will come to market faster as well, he added.

Frey has pioneered a number of approaches to Alzheimer's treatment deemed promising by the federal government, including intranasal administration of insulin. By recognizing that new approaches may need to be judged by different standards, he said, the FDA will promote the idea that "it's not going to be a single treatment that's going to be a cure, but a series of improving treatments" that may work better for some patients than others.